The general approach required for this Indefinite Delivery Indefinite Quantity (IDIQ) Contract initiative will be to first establish a small team of clinical trial sites and subsequently to test identified interventions (pharmacologic and/or non-pharmacologic) in adequately powered Proof of Concept trials in humans. Trials will be initiated after promising interventions are identified by members of the team (including the NIMH Intramural Research Program), and approved by the RAPID steering committee and the NIMH Contracting Officers Representative (COR) (previously referred to as the Government Program Officer). This initiative will leverage the development of rapidly-acting treatments (demonstrable clinical improvement within 72 hours of administration) for severe, treatment-resistant depression. To establish a small team of clinical trials sites to study Rapidly-Acting Treatments for Depression (i.e., the RAPID-team) that will focus on identifying and testing promising interventions (pharmacologic and/or non-pharmacological) that produce a substantial anti-depressant effect within 72 hours of initial administration. To perform randomized clinical trials testing such promising interventions (other than Ketamine Hydrochloride or sleep deprivation (total or partial)) in a well-characterized cohort of adult subjects (age 18-60) diagnosed with treatment-resistant depression. 2. A secondary objective would be: To further study and evaluate interventions that showed efficacy in a RAPID-team Proof of Concept trial in a larger clinical trial.